Clinical Implications of Lysyl Oxidase-Like Protein 2 Expression in Pancreatic Cancer

Tanaka, Nobutake; Yamada, Suguru; Sonohara, Fuminori; Suenaga, Masaya; Hayashi, Masamichi; Takami, Hideki; Niwa, Yasumasa; Hattori, Norifumi; Iwata, Nakao; Kanda, Mitsuro; Tanaka, Chie; Kobayashi, Daisuke; Nakayama, Goro; Koike, Masahiko; Fujiwara, Michitaka; Fujii, Tsutomu; Kodera, Yasuhiro

doi:10.1038/s41598-018-28253-9

Cited by 32 publications

(45 citation statements)

References 31 publications

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“…22 Herein, we found that salidroside suppressed the expression of entire LOX family members, however, more effectively inhibited LOXL2 in a PC cell line (BxPC-3) (Figure 1). 22 Herein, we found that salidroside suppressed the expression of entire LOX family members, however, more effectively inhibited LOXL2 in a PC cell line (BxPC-3) (Figure 1).…”

Section: Discussionmentioning

confidence: 77%

Salidroside ameliorated hypoxia‐induced tumorigenesis of BxPC‐3 cells via downregulating hypoxia‐inducible factor (HIF)‐1α and LOXL2

Chen

Kou

et al. 2019

J of Cellular Biochemistry

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Herein, we found that salidroside suppressed hypoxia‐inducible factor 1 alpha (HIF‐1α) and lysyl oxidase‐like protein 2 (LOXL2) within human pancreatic cancer BxPC‐3 cells cultured both under normoxia and hypoxia condition. To investigate the effect of salidroside on tumorigenesis of BxPC‐3 cells and whether HIF‐1α and LXCL2 were involved in this process, cells transfected with or without LOXL2 overexpression vector, were treated with 50 μg/mL of salidroside or 50 μM of KC7F2 (a HIF‐1α inhibitor) under hypoxia. Cell viability and invasion were assessed using CCK‐8 and Transwell chamber assay, respectively. Expression of E‐cadherin and matrix metalloproteinase 2/9 (MMP 2/9) was determined, by Western blot analysis, to assess cell mobility at molecular levels. We confirmed that hypoxia increased LOXL2 and induced tumorigenesis of BxPC‐3 cells, as evidenced by promoted cell proliferation and invasion, enhanced MMP2/9 while reduced E‐cadherin. Interestingly, hypoxia‐induced carcinogenesis was significantly retarded by both salidroside and KC7F2, however, enhanced with LOXL2 overexpression. Besides, salidroside and KC7F2 reduced LOXL2, and reversed the tumorigenesis of BxPC‐3 cells induced by LOXL2 overexpression. Given the inhibitory effect of salidroside on HIF‐1α expression, our data suggested that: (1) LOXL2 was the mechanism, whereby salidroside and KC7F2 showed inhibitory effect on cancer progression of BxPC‐3 cells; (2) salidroside exerted its anticancer effect, most likely, by a HIF‐1α/LOXL2 pathway. In conclusion, salidroside was a novel therapeutic drug in pancreatic cancer, and downregulation of HIF‐1α and LXCL2 was the underlying mechanism.

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Section: Discussionmentioning

confidence: 77%

Salidroside ameliorated hypoxia‐induced tumorigenesis of BxPC‐3 cells via downregulating hypoxia‐inducible factor (HIF)‐1α and LOXL2

Chen

Kou

et al. 2019

J of Cellular Biochemistry

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“…We have previously reported that the EMT status is one of the independent prognostic factors for surgically resected PCs. The expression of lysyl oxidase homolog 2 (LOXL2), one of the important regulators of EMT, was significantly related to PC patients' survival and it is one of the putative therapeutic targets (4,20). In addition, evidence supports that EMT may mediate chemoresistance in PC and defining the EMT status of each PC patient might contribute to suitable multidisciplinary therapy (21,22).…”

Section: Discussionmentioning

confidence: 99%

Exploration of Exosomal Micro RNA Biomarkers Related to Epithelial-to-Mesenchymal Transition in Pancreatic Cancer

et al. 2020

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Background/Aim: Epithelial-to-mesenchymal transition (EMT) plays important roles in cancer progression. This study aimed to identify the exosomal miRNA (exo-miRNA) profiles related to the EMT status in pancreatic cancer (PC). Materials and Methods: Comprehensive exo-miRNA-expression profiles in the culture media of PC cell lines were analyzed through microarray technology. The identified miRNAs were analyzed to investigate their clinical implication using The Cancer Genome Atlas (TCGA) dataset and clinical samples. Results: We prioritized 291 exo-miRNAs differentially expressed between epithelial and mesenchymal cell types. Among them, survival analysis based on the TCGA dataset revealed that mir-196b and mir-204 significantly stratify the prognosis of PC cases. In addition, analysis of cell lines indicated miR-196b-3p as a mesenchymal marker and miR-204-3p as an epithelial marker. Finally, we demonstrated that miR-196b-3p and miR-204-3p in serum exosomes were differentially expressed among intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and PC. Conclusion: Serum exo-miRNA biomarkers potentially identify the pancreatic tumor status through less-invasive methods.

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“…38 Among the LOX family members, LOXL2 has been considered to be a critical regulatory factor in tumor initiation and progression. 17,39,40 In addition, several LOXL2 splice variants have been found in esophageal squamous cell carcinoma, such as the variant lacking exon 13 and the variant with a deletion of 72 nucleotides, which contribute to tumor progression by a novel molecular mechanism distinct from canonical-type LOXL2. 17,39,40 In addition, several LOXL2 splice variants have been found in esophageal squamous cell carcinoma, such as the variant lacking exon 13 and the variant with a deletion of 72 nucleotides, which contribute to tumor progression by a novel molecular mechanism distinct from canonical-type LOXL2.…”

Section: Discussionmentioning

confidence: 99%

“…17 In previous studies, it has been demonstrated that LOXL2 was associated with poor prognosis in a variety of tumors and that overexpression of LOXL2 can promote the invasion and metastatic activity of cancer cells. 17,39,40 In addition, several LOXL2 splice variants have been found in esophageal squamous cell carcinoma, such as the variant lacking exon 13 and the variant with a deletion of 72 nucleotides, which contribute to tumor progression by a novel molecular mechanism distinct from canonical-type LOXL2. 19,22 In the current study, we used the loss-of-function and gain-of-function experiments to elucidate the role of the novel LOXL2 variant identified from TCGA HPVnegative HNSCC data.…”

Section: Discussionmentioning

confidence: 99%

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

Liu

Guo

Sakai

et al. 2019

Cancer

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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXlike (LOXL) 2 (LOXL2) demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC. Cancer 2020;126:737-748.

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Clinical Implications of Lysyl Oxidase-Like Protein 2 Expression in Pancreatic Cancer

Cited by 32 publications

References 31 publications

Salidroside ameliorated hypoxia‐induced tumorigenesis of BxPC‐3 cells via downregulating hypoxia‐inducible factor (HIF)‐1α and LOXL2

Salidroside ameliorated hypoxia‐induced tumorigenesis of BxPC‐3 cells via downregulating hypoxia‐inducible factor (HIF)‐1α and LOXL2

Exploration of Exosomal Micro RNA Biomarkers Related to Epithelial-to-Mesenchymal Transition in Pancreatic Cancer

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

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